Mechanisms Of Action Of The Trefoil Peptides In Promoting Healing In Models Of Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$365,270.00
Summary
Preliminary experiments from our laboratory have shown that members of a family of small proteins called trefoil peptides, found naturally in the stomach, intestine and colon, are able to shorten the healing time of ulcers and reduce inflammation, in an animal model of inflammatory bowel disease. Crohn's disease and ulcerative colitis together make up the human inflammatory bowel diseases, or IBD for short. They afflict many members of the community, are debilitating, expensive to treat, and cur ....Preliminary experiments from our laboratory have shown that members of a family of small proteins called trefoil peptides, found naturally in the stomach, intestine and colon, are able to shorten the healing time of ulcers and reduce inflammation, in an animal model of inflammatory bowel disease. Crohn's disease and ulcerative colitis together make up the human inflammatory bowel diseases, or IBD for short. They afflict many members of the community, are debilitating, expensive to treat, and current treatments like corticosteroids and suppressors of the immune system have unpleasant and health-threatening side effects. There are therefore good reasons for the development of new forms of therapy which will be better tolerated and which are specific in their actions. We believe that the trefoil peptides may be good candidates on which new treatments for inflammatory disease might be based. The studies outlined in this proposal will test the best route of administration, and how often to give trefoil peptides in order to relieve the symptoms of experimental IBD. In addition the effectiveness of the trefoils will be compared to other agents currently used in IBD treatment, or which are known to relieve inflammation or speed the healing of the ulcerated colon. We will also carry out experiments designed to work out the mechanisms by which the trefoils' healing effects are mediated, and finally we will characterise a new member of the trefoil peptide family which we have recently discovered.Read moreRead less
Elucidation Of Mechanisms By Which Fibre Promotes Or Protects From Colorectal Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
In a carefully controlled animal model of colon cancer development, dietary fibre can increase or decrease the likelihood of colon cancer development. It depends upon the type of fibre being fed to the animal. The mechanisms by which fibres can increase or decrease the likelihood of colon cancer developing are, however, poorly understood. In this proposal, we will attempt to elucidate at least some of the mechanisms. We plan to define whether animals consuming fibres that increase cancer develop ....In a carefully controlled animal model of colon cancer development, dietary fibre can increase or decrease the likelihood of colon cancer development. It depends upon the type of fibre being fed to the animal. The mechanisms by which fibres can increase or decrease the likelihood of colon cancer developing are, however, poorly understood. In this proposal, we will attempt to elucidate at least some of the mechanisms. We plan to define whether animals consuming fibres that increase cancer development have factors in their faeces that affect the health of the cells that line the colon (the ones that form the cancers). This will be examined in both the test tube and in healthy rats. Whether fibres influence the access of these factors to the lining cells by sequestering or hiding the factors in the jelly-like consistency some fibres produce in the colon will also be examined. The results will help identify conditions in the faeces that alter the susceptibility of colons to developing cancer. By identifying these conditions, we can then apply our knowledge to human subjects, so that we might be able to identify those at a higher or lower risk of developing colon cancer and we can advise and (subsequently prove) ways of modifying diet to reduce the risk of colon cancer.Read moreRead less
Investigation Into The Alternative Splicing Of Steroid Hormone Regulated Genes In Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Steroid hormones have imortant roles in breast tissue growth and differentiation. We have identified several proteins called PRMT6 and CAPER's , that are involved in steroid hormone signaling and control the alternative splicing of RNA, the process in which several different proteins can be produced from a single gene. Our aim is to study these proteins in an effort to understand how they influence alternative splicing and to identify genes they control in relation to breast cancer.
Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less
Physiological Mechanisms Of Efficacy Of Cervical Flexor Muscle Retraining
Funder
National Health and Medical Research Council
Funding Amount
$264,750.00
Summary
Neck pain is a significant problem in society and its frequency is beginning to match the proportions of back pain, probably reflecting our increasingly sedentary lifestyles. Several problems have been identified in the muscle system in persons who suffer from neck pain. Therapeutic exercise has been found to have benefit in preventing and relieving pain and improving the neck function. Currently there are several, quite different methods of exercise and there is controversy regarding how therap ....Neck pain is a significant problem in society and its frequency is beginning to match the proportions of back pain, probably reflecting our increasingly sedentary lifestyles. Several problems have been identified in the muscle system in persons who suffer from neck pain. Therapeutic exercise has been found to have benefit in preventing and relieving pain and improving the neck function. Currently there are several, quite different methods of exercise and there is controversy regarding how therapeutic exercise works. It has been argued that parameters such as changes in muscle strength, endurance, joint position sense or muscle coordination may be responsible for the clinical efficacy. It is difficult to disentangle the effective component of exercise strategies and thus prescribe the most effective exercise strategies. This series of experiments will evaluate the physiological factors that change with a specific exercise intervention and to compare different exercise modalities in order to identify the most effective means to induce these changes. Cervical muscle training, using a proven exercise intervention strategy for chronic neck pain and headache, has been chosen as the model to investigate these questions. This exercise strategy has been chosen not only because it has been shown to be effective, but also because it does not conform to contemporary rationales for strength or endurance training. Thus while effective in relieving pain, it is unlikely to produce changes in these parameters. Thus other mechanisms are likely to be responsible for the clinical change. This research stands to make a significant contribution to exercise therapeutics by identifying the effective components of different exercise methods and investigating the pain relieving effects of the specific exercise. This knowledge will lead to the construction of a research based exercise program for neck pain patients, rather than have the current situation of often arbitrary choice of exercise.Read moreRead less
Peptidase Inhibitor 16: A New Biomarker For Human Treg
Funder
National Health and Medical Research Council
Funding Amount
$391,262.00
Summary
As autoimmune diseases including type 1 diabetes and IBD are on the increase, there is still great need for novel diagnostic or therapeutic molecules. We have discovered a novel role for a protein called PI16, which we believe is a biomarker for natural regulatory T cells. These cells police the immune system, preventing inappropriate immune responses such as those that cause autoimmune diseases. This project will confirm its suitability for use as a diagnostic or therapeutic biomarker.
Pharmacological Targeting Via AKT, PTEN, And TGF-beta Pathway Integration Using Novel Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$634,875.00
Summary
We have identified potentially important interactions of cellular pathways that vary between individual sufferers, but which also provide common molecular targets for novel drug development. Our suite of novel and potent drugs that markedly and selectively inhibit cancer cell growth will be studied to determine if these pharmaceutical agents act to inhibit tumour cell proliferation by targeting common effector molecules of integrated cellular pathways.
Steroid hormones, such as oestrogen and cortisol, act in the body by binding a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified termed SRA, which remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins t ....Steroid hormones, such as oestrogen and cortisol, act in the body by binding a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified termed SRA, which remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins that bind to SRA in cancer cells, and may well play a critical role in regulating how SRA modulates genes. This project seeks to understand how this family interacts with SRA, the functional effects on breast cancer cells, and the detailed 3-dimensional structure of the family members coupled with SRA. This work will provide novel insight into how SRA regulates steroid hormone action, and may create new potential avenues for developing therapeutics in breast cancer.Read moreRead less